In 1925, he moved to New York City, where he became manager and general counsel of Comerford Theatres, a chain of movie theaters owned by his relative Michael Comerford.

In New York, Walker expanded his political activities, and became an early supporter of Franklin D. Roosevelt. In 1931, he co-founded the Roosevelt for President Society. In 1932, he became Treasurer of the Democratic National Committee (DNC). Until Roosevelt's death, Walker was one of his closest advisers.

In 1940, Walker became Postmaster General (succeeding James Farley, who had also been DNC Chairman and Roosevelt's campaign manager). As Postmaster General, Walker continued his role as political adviser, often taking part in matters far removed from the Post Office. For instance, during the negotiations which preceded the December 1941 attack on Pearl Harbor, he was in regular contact with Japanese Ambassador Nomura.[1]

In 1943, Walker also became Chairman of the DNC, serving until 1944. In 1944, he stepped down from the DNC, and was succeeded by Robert Hannegan.

In May 1945, Walker announced his retirement as Postmaster General, to allow President Harry Truman to appoint his own candidate to the office. Truman selected Hannegan to succeed Walker in this office too, effective July 1.

Later in 1945, Truman appointed Walker as a member of the first U.S. delegation to the United Nations.